Cancer immunotherapy is among the biggest breakthroughs in the last decade. However, the success of single agent immunotherapy has so far been limited to a few solid malignancies, including melanoma, renal cell carcinoma, and non-small cell lung cancer. One difference between cancers that have responded to checkpoint inhibitors and cancers like pancreatic ductal adenocarcinoma (PDA) that have not is the immune status of the tumor microenvironment (TME). PDA, like many other solid malignancies, was considered to be non-immunogenic. We recently reported that PDA tumors resected just two weeks following a single neoadjuvant dose of a granulocyte-macrophage colony stimulating factor (GM-CSF) secreting PDA vaccine (GVAX) induces the formation of novel immunologically active tertiary lymphoid aggregates, organized lymph node-like structures that are not observed in tumor tissue resected from unvaccinated patients. This prior study showed for the first time that a vaccine-based immunotherapy can reprogram an immunologically quiescent TME into an immunologically active TME. However, activated T cells in the PDA TME secrete interferon-?, which in turn upregulates PD-1/PD-L1. Thus, we hypothesize that treatment with GVAX primes the PDA TME for anti-PD-1/PD-L1-targeted therapy. Supporting this hypothesis, our preclinical studies showed that combining anti-PD-1 or PD-L1 antibodies with vaccines enhances the frequency of effector T cells infiltrating PDAs and the cure rate in PDA tumor-bearing mice. To further test this hypothesis, we will enroll and randomize 50 patients with resectable PDAs to a 2-arm clinical trial to receive either one neoadjuvant treatment with GVAX plus Cytoxan (Cy) alone or in combination with an anti-PD-1 antibody (nivolumab) two weeks prior to surgical resection of their PDAs, followed by five additional adjuvant immunotherapies. We will compare PDA specimens from a pre-treatment core biopsy and the surgically resected tumors and evaluate primary endpoint (IL17A expression in vaccine-induced lymphoid aggregates) and secondary endpoints (safety, disease free survival and overall survival) of this clinical trial. We will assess the effects of anti-PD-1 antibody blockade in combination with Cy/GVAX on the PD-L1/PD-1 associated pathways, vaccine-induced immune regulatory signatures, and peripheral and intratumoral antigen specific T cell responses. The results are expected to determine the role of modulating the PD-1/PD-L1 pathway in the PDA TME, to identify alternate regulatory pathways that may compensate for PD-1 blockade, and to identify signatures of immune response within the PDA TME. If the combinatorial treatment arm demonstrates enhanced IL17A expression in lymphoid aggregates and/or better survival than Cy/GVAX alone, we will compare the two treatment arms against standard of care in a randomized study with a sample size adequate to estimate an improvement in clinical efficacy.